AICA‐Riboside: Safety, Tolerance, and Pharmacokinetics of a Novel Adenosine‐Regulating Agent

Abstract

AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.

Immunomodulatory Effect of Combination Therapy with Lovastatin and 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Alleviates Neurodegeneration in Experimental Autoimmune Encephalomyelitis

“…As we reported previously, to prevent the progression of EAE, optimal doses of lovastatin and AICAR were Ն2 mg/kg 17,19,27 and Ն100 mg/kg, 22,29 respectively, when administered individually. Therefore, we first evaluated the therapeutic efficacy of the suboptimal dose of lovastatin (1 mg/kg) and AICAR (50 mg/kg) in combination or individually and compared those findings with their optimal dose effects.…”

5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…The safety, tolerance, and pharmacokinetics of i.v. doses of 10 -100 mg/kg AICAR in human health have been reported previously (49). Metformin and the peroxisome proliferator-activated receptor ␥ agonist rosiglitazone have been reported to activate AMPK and are believed to contribute to their insulin-sensitizing actions in diabetic subjects (8).…”

Metabolic Stress Boosts Humoral Responses In Vivo Independently of Inflammasome and Inflammatory Reaction

“…Recently, this compound has been shown to cause a significant decrease in intracellular ATP levels in several human and murine cell lines (32)(33)(34). Despite the lack of precise information concerning its mode of action, AICAR has been used extensively in animals and human clinical studies as a putative agent thought to protect the heart, lung, and small intestine against ischemic damage (35,36), and the safety, tolerance, and pharmacokinetics of this compound are well described (37). The ability of AICAR to increase T cell-dependent humoral responses in vivo therefore was evaluated.…”